Environmental contaminants that mimic the effects of estrogen have been suggested to contribute to the high incidence of breast cancer in Western populations. In both in vitro and in vivo experiments, cadmium has been shown to possess potent estrogen-like activity, including proliferation of breast cancer cells, activation and increased expression of estrogen regulated genes, and activation of the estrogen receptor-1. Further, cadmium is classified as a known human carcinogen by the International Agency for Research on Cancer. This combination of estrogenic and carcinogenic activity makes cadmium a contaminant of particularly high concern for breast cancer. One modest-sized epidemiologic study suggests risk at cadmium exposure levels common to the upper quartile of the general population implying that cadmium may play a substantial role in breast cancer; however this study used urine cadmium collected after diagnosis. As a result, it has been questioned whether increased cadmium is a risk factor for breast cancer, or whether it reflects the effects of treatment or disease. In light of mechanistic and preliminary epidemiologic evidence supporting a cadmium-breast cancer relationship, this project aims to rigorously investigate the association between urinary cadmium levels collected prediagnostically and risk of breast cancer in a case-cohort study population from the Danish Diet Cancer and Health (DCH) prospective cohort. This is one of the few, if not only, cohorts in the world with adequate power for investigating breast cancer along with urine samples collected pre-diagnostically and available on all participants. Among the 57,053 members of the DCH cohort we will identify 900 cases of female breast cancer, and randomly select 900 women as a comparison group (sub-cohort) according to the efficient case-cohort design. Female population will be limited to those postmenopausal at baseline because most breast cancer cases occur in postmenopausal women. Urine samples will be analyzed for cadmium, other metals, and creatinine. This study will provide reliable and valuable insight into the hypothesized association between cadmium exposure in a general population and breast cancer and will assess whether zinc intake and smoking history modify these relationships. Analyses will also be stratified by ductal and lobular histology, in situ / invasive status, estrogen receptor positive, stage of cancer, along with other variables to investigate sensitivity of results and effect modification. The proposed study will address pressing questions posed by recent results and will overcome several methodological limitations of previous studies related to precision of the exposure assessment, study size, and possible bias in previous retrospective designs. If the study shows an association between urinary cadmium level and risk of breast cancer, there is great potential for prevention with more extensive regulation to avoid population exposure, since primary sources of general population exposure to cadmium are well recognized. PUBLIC HEALTH RELEVANCE: Breast cancer accounts for 200,000 new cases and 40,000 deaths in the United States each year; few modifiable risk factors have been identified. Mechanistic and early epidemiologic evidence suggest that cadmium, a known lung carcinogen, mimics endocrine hormones and may contribute to the high incidence rates of breast cancer in Western industrialized nations. This study seeks to shed light on whether urinary cadmium, a biomarker of decades-long exposure, is associated with breast cancer using a case-cohort epidemiologic study design and the Danish Diet and Cancer Cohort, one of the few cohorts in the world with adequate power for investigating cancer outcomes along with urine samples collected pre-diagnostically and available on all participants.